During the past four years of support we have made tremendous progress, have achieved the goals o the original proposal and have been able to go far beyond the proposed aims. Among these achievements we were able to develop a mouse model of CLL, to establish the role of the Tcl1/Akt pathway in the pathogenesis of CLL, to discover the role of miR genes in CLL, to dissect the genetics of 6q alterations in CLL with poor prognosis, to discover the ARLTS1 tumor suppressor gene at 13q14 and a germline mutation of this gene that predisposes to a variety of human cancers including CLL, and to develop a miR gene chip to investigate patterns of miR expression in this malignancy. In this renewal application we propose: 1) to continue our studies to dissect the genetics of sporadic and familial CLL; 2) to establish the role of miR genes in sporadic and familial CLL.